1. 11/30/2018
Using Delayed Start Design and Analysis to Investigate Potential Disease Modifying Effects in Alzheimer’s Disease

2. Alzheimer’s Disease (AD)
Type of dementia causing problems with memory, cognition, and behavior
Symptoms typically develop slowly and worsen over time
No cure
Approved therapies
transient benefits on symptoms
do not slow progression of disease
Current research efforts aimed at modifying disease course

3. Delayed Start Trial Designs
Suggested by Paul Leber (1997)
Used in Parkinson’s Disease research (ADAGIO)
Endorsed in Feb 2018 regulatory guidance
FDA: Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry
EMA: Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease

6. Analysis Approach
Include all randomized patients in one model from randomization to end of Delayed Start (DS) period and make three tests:
Treatment difference: end of placebo-controlled period (1)
Treatment difference: end of delayed start period (2)
Non-inferiority comparison of 2 and 50% of 1 (Ha: 2 – 50% of 1 > 0) tested with a one-sided 90% LCL
Three tests combine to give weight of evidence

7. EXPEDITION and EXPEDITION2 Studies
Identical phase 3 studies run concurrently
Mild to moderate patients
Early Start phase was 18 months
Analyses of mild AD participants indicated possible benefits

8. EXPEDITION and EXPEDITION2 Cognition Results
11/30/2018
Month
Test 1
(p-val)
Test 2
Test 3
(-LCL)
0.002 na 6
0.006
0.52 12
0.009
0.63 24
0.032
0.46 36
0.043
0.55 48
0.047
0.69
Source: prd/ly /h8a_mc_lzao/final/programs_stat/tfl_output/rmdelay2_adas14_pooled.rtf

9. EXPEDITION and EXPEDITION2 Function Results
11/30/2018
Month
Test 1
(p-val)
Test 2
Test 3
(LCL)
0.040 na 6
0.045
0.09 12
0.019
0.35 24
0.119
-0.23 36
-0.21 48
0.014
0.94
Source: prd/ly /h8a_mc_lzao/final/programs_stat/tfl_output/rmdelay2_iadl_pooled.rtf

10. EXPEDITION3 Results Phase 3 study in Mild AD patients
Early Start phase 18 months
Primary objective was not met

11. EXPEDITION3 Cognition Results
11/30/2018
Month
Test 1
(p-val)
Test 2
Test 3
(LCL)
0.109 na 6
0.516
-0.51 9
0.332
-1.33
Source: prd/ly /h8a_mc_lzax/final/output/shared/rmdelay_adas14_9m1_2_ho3.rtf

12. EXPEDITION3 Function Results
11/30/2018
Month
Test 1
(p-val)
Test 2
Test 3
(LCL)
0.019 na 6
0.044
0.07 9
0.247
-0.41
Source: prd/ly /h8a_mc_lzax/final/output/shared/rmdelay_iadl_9m1_2_ho3.rtf

13. Conclusions
Delayed Start clinical trial designs can be used to show disease modification
Tests 1-3 provide weight of evidence for disease modification
Smaller treatment differences prior to delayed start period are problematic to show disease modification

14. References
Leber P. Slowing the progression of Alzheimer disease: methodological issues. Alzheimer Dis Assoc Disord. 1997; 11: S10–21.
Bhattaram VA, Siddiqui O, Kapcala LP, Gobburu JV. Endpoints and analyses to discern disease modifying drug effects in early Parkinson’s disease. AAPS J. 2009; 11: 456–464.
Liu-Seifert H, Andersen SW, Lipkovich I, Holdridge KC, Siemers E (2015) A Novel Approach to Delayed-Start Analyses for Demonstrating Disease-Modifying Effects in Alzheimer’s Disease. PLoS ONE 10(3): e doi: /journal.pone
Liu-Seifert H, Siemers E, Holdridge K, Andersen S, Lipkovich I, Carlson C, Sethuraman G, Hoog S, Hayduk R, Doody R, Aisen P. (2015) Delayed-start analysis: Mild Alzheimer’s disease patients in solanezumab trials, 3.5 years. Alzheimer’s& Dementia: Translational Research & Clinical Interventions. 2015; 1-11.

15. Contact Info
Scott Andersen
Eli Lilly and Company